ATTACH = Anti-TNF-α Therapy Against Chronic Heart failure; CHF = congestive heart failure; CVD = cardiovascular disease; IL = interleukin; LV = left ventricular; LVEF = left ventricular
Trang 1ATTACH = Anti-TNF-α Therapy Against Chronic Heart failure; CHF = congestive heart failure; CVD = cardiovascular disease; IL = interleukin; LV = left ventricular; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MMP = matrix metalloproteinase; OA = osteoarthritis; RA = rheumatoid arthritis; RECOVER = Research into Etanercept: Cytokine Antagonism in Ventricular Dysfunction Trial; RENNAISANCE = Randomized Etanercept North American Strategy to Study Antagonism of Cytokines; RF rheumatoid factor; TACE = TNF-α converting enzyme; TIMP = tissue inhibitor of matrix metalloproteinase; TNF-α = tumor necrosis factor-α
Abstract
Data from population- and clinic-based epidemiologic studies of
rheumatoid arthritis patients suggest that individuals with rheumatoid
arthritis are at risk for developing clinically evident congestive heart
failure Many established risk factors for congestive heart failure are
over-represented in rheumatoid arthritis and likely account for some
of the increased risk observed In particular, data from animal models
of cytokine-induced congestive heart failure have implicated the
same inflammatory cytokines produced in abundance by rheumatoid
synovium as the driving force behind maladaptive processes in the
myocardium leading to congestive heart failure At present, however,
the direct effects of inflammatory cytokines (and rheumatoid arthritis
therapies) on the myocardia of rheumatoid arthritis patients are
incompletely understood
Introduction
Unique cardiac complications of rheumatoid arthritis (RA),
such as cardiac rheumatoid nodules, have been recognized
for over a century It has only been appreciated in the last
decades, however, that certain chronic autoimmune
inflam-matory diseases, such as RA and systemic lupus
erythema-tosis, increase the risk of developing cardiovascular disease
(CVD), particularly atherosclerosis and congestive heart
failure (CHF) [1-5] In fact, striking commonalities in the
cellular and cytokine profiles of the rheumatoid synovial lesion
and atherosclerotic plaque [6-8] have prompted speculation
that the inflammatory pathways of RA may initiate and/or
accelerate plaque formation and that this effect may be
ameliorated by anti-inflammatory therapies [9]
The link between RA and CHF is less well studied The CHF
phenotype can evolve from a variety of pathogenic conditions,
many of which may be promoted by the RA disease process
Yet to date, only a handful of investigations have attempted to
dissect this complex issue A particular source of confusion has been the apparent contradiction between pre-clinical studies linking inflammation to CHF and the lack of efficacy of anti-cytokine therapy in clinical trials in advanced CHF (discussed below) Because anti-cytokine therapy has become a cornerstone in the treatment of RA, it is particularly critical to understand the contribution of cytokine-induced inflammation to myocardial structure and function in RA Here, we review the current literature on the epidemiology of CHF in RA with an emphasis on the pathogenesis of cytokine induced myocardial dysfunction
Epidemiology of congestive heart failure:
general considerations
The epidemiology of CHF in RA, and the limitations of the available data, are better appreciated in the context of estimates of CHF in the general population The prevalence
of CHF in western countries appears to have been increasing over the past few decades, due primarily to increased longevity rather than to a change in incidence rates [10] In the United States, more than 400,000 new cases of CHF are identified each year and added to the estimated 2.5 to
5 million Americans with prevalent CHF [11,12], yielding an overall prevalence of 1.1% to 2% of the population Nearly 300,000 deaths in the US are attributed to CHF annually [10] For persons over the age of 65 years, CHF is the most frequent cause of hospitalization [11,13]
Incidence rates of CHF vary among published reports, presumably reflecting differences in the populations studied, diagnostic criteria used, and temporal trends in coding practices for reimbursement [14] Recent data from several community-based cohorts [15-18] have yielded an estimated
Review
Myocardial dysfunction in rheumatoid arthritis: epidemiology
and pathogenesis
Jon T Giles1, Verônica Fernandes2, Joao AC Lima2and Joan M Bathon1
1Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
2Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
Corresponding author: Jon T Giles, gilesjont@jhmi.edu
Published: 24 August 2005 Arthritis Research & Therapy 2005, 7:195-207 (DOI 10.1186/ar1814)
This article is online at http://arthritis-research.com/content/7/5/195
© 2005 BioMed Central Ltd
Trang 2age-adjusted incidence of CHF of 3.4 to 17.6 per 1,000
person-years for men and 2.4 to 12.5 per 1,000 person-years
for women The wide range in rates reflects, at least in part,
differences in diagnostic criteria used from study to study For
example, age-adjusted incidence rates based on the
Framingham diagnostic criteria for heart failure [15,16,18,19]
(Table 1) were between 2 and 4 per 1,000 person-years,
whereas rates based on less stringent criteria were three- to
four-fold higher [17]
The incidence of CHF increases with age [20,21]; 88% of
affected individuals are over the age of 65 years, and 49% are
over 80 years at diagnosis [20] The remaining lifetime risk of
developing CHF at all index ages from 40 through 80 years of
age is between 20% and 33%, and is roughly equal for men
and women [17,22] Levy et al [15] have shown that over the
past 50 years the incidence of CHF has declined among
women but not among men This lack of decline in CHF
incidence among men is largely attributable to advances in the
management of acute myocardial infarction, diabetes, and
hypertension that have led to an overall decrease in mortality
rates from these disorders while adding to the incidence of
CHF [23] Survival after the onset of CHF has improved in
both sexes [15] Factors contributing to the decrease in CHF
mortality include improved access to care, the introduction of
effective therapies, and improved care of comorbid conditions
[15] Despite these encouraging trends, mortality rates of
patients with CHF remain alarmingly high Recent reports from
community-based cohorts [15-18] estimate age-adjusted
one-and five-year CHF mortality at 23% to 27% one-and 45% to 65%, respectively For women in these series, survival was slightly better than [15,16] or equal to [17,18] men
Epidemiology of congestive heart failure in rheumatoid arthritis
Fewer statistics on incidence and prevalence rates for CHF in patients with RA are available and are derived from a handful
of population-based [24-26] and clinic-based RA cohorts
[5,27,28] Gabriel et al [24] estimated the incidence of CHF
among all RA patients in Olmsted County, Minnesota, from data abstracted from medical records Between 1955 and
1985, 78 cases of incident CHF were identified among 450 prevalent cases of RA compared to 54 cases among the same number of non-RA community controls matched for age, sex, and baseline comorbidity, yielding a relative risk of 1.60 (95% CI 1.12-2.27) In contrast, the risk of incident CHF in patients with osteoarthritis (OA), a non-inflammatory arthritis, was not increased compared to non-OA community controls [24] In a follow-up retrospective review of the same cohort extended to 1995, now using the Framingham
diagnostic criteria for CHF (Table 1), Nicola et al [26]
confirmed an increased risk of incident CHF in both rheumatoid factor (RF) negative and positive RA patients (hazards ratio 1.34 and 2.29, respectively) compared to
non-RA controls adjusted for age, sex, and CV risk factors Incident CHF risk remained elevated after further adjustment for comorbid ischemic heart disease (hazards ratio 1.28 and 2.59 for RF negative and positive RA patients, respectively), although the risk relationship was no longer statistically significant for RF negative patients in this model [26]
In a combined cohort of RA patients from community-based
practices and drug safety monitoring studies (n = 9093), Wolfe et al [5] estimated an adjusted lifetime relative risk of
CHF in patients with RA of 1.43 (95% CI 1.24-1.33) compared with OA controls The adjusted lifetime prevalence
of CHF in the RA population was 2.34% compared to 1.64%
in OA controls Data were collected via patient survey of self-reported, physician-diagnosed CHF, and confirmed by review
of a random sample of medical records in 50% of patients reporting CVD events In a subsequent analysis [27], in which
the drug safety cohort represented a third (n = 4,307) of the total sample (n = 13,171), Wolfe et al reported an adjusted
frequency of CHF of 3.9% (95% CI 3.4-4.3%) in RA patients compared to 2.3% (95% CI 1.6-3.3%) in controls with knee
or hip OA Factors associated with prevalent and incident CHF were those typically associated with CHF in the non-RA population (e.g., age, male gender, hypertension, coronary artery disease, diabetes, and smoking) while RA-related measures (patient-reported disability, pain, and RA global severity) were also associated with prevalent and incident CHF As data were collected by mailed questionnaire, objective measures of RA disease activity (e.g., swollen and tender joint counts and serum inflammatory markers) were not available to assess as predictor variables
Table 1
Framingham diagnostic criteria for congestive heart failure [19]
Major criteria
Paroxysmal nocturnal dyspnea
Neck vein distension
Pulmonary rales
Radiographic cardiomegaly (chest radiography)
Acute pulmonary edema
Third heart sound gallop
Central venous pressure > 16 cm water
Circulation time ≥ 25 seconds
Hepatojugular reflux
Weight loss ≥ 4.5 kg in 5 days in response to treatment with diuretics
Paroxysmal nocturnal dyspnea
Minor criteria
Bilateral ankle edema
Nocturnal cough
Dyspnea on ordinary exertion
Hepatomegaly
Pleural effusion
Decrease in vital capacity by 33% of maximum
Heart rate ≥ 120 beats per minute
Bilateral ankle edema
Nocturnal cough
Two major or one major and two minor criteria are required for a
clinical diagnosis of CHF
Trang 3Indeed, the impact of CHF in RA may be under-appreciated
due to excess CHF related mortality Mutru et al [28] first
reported a higher rate of CHF-attributed mortality in RA
patients compared to age- and gender-matched controls with
CHF for both males (P = 0.004) and females (P = 0.042) In
a recent report, Nicola et al [29] found that CHF preceded
nearly two-thirds of the excess CVD associated deaths in RA
patients compared to age- and gender-matched controls
These unexpected results alone emphasize a need for greater
understanding of the dynamics of myocardial dysfunction in
RA and suggest that survivor-bias may serve to
underestimate the true extent of CHF in the RA population
An important limitation of each of these studies is in the
method chosen to ascertain the diagnosis of CHF The
application of clinical criteria alone for the diagnosis of CHF
is too imprecise, as demonstrated by one study [30] in which
a false positive diagnosis of CHF was made by primary care
providers in over one-third of patients Current guidelines
[10] advocate the need for Doppler echocardiographic
confirmation of any diagnosis of CHF when suspected
clinically Reliance on clinical diagnostic criteria alone may
result in over-diagnosis of CHF in some case In others, CHF
may be under-diagnosed when dependent ankle edema is
mistaken for joint swelling, chronic pulmonary congestion is
misinterpreted as rheumatoid lung involvement, and exertional
dyspnea is masked by a sedentary lifestyle due to painful joint
deformities Nevertheless, on balance, the available data
support higher prevalence and incidence rates of CHF in RA
patients compared to matched controls without RA Many
factors unique to or over-represented in RA patients may
explain, at least in part, why the myocardium is at risk in RA In
addition, an analysis of the relative contributions of each of
these risk factors and associated biomarkers to the
development of CHF in RA patients invites speculation into
the underlying pathophysiologic mechanisms leading to
myocardial dysfunction
Risk factors, echocardiographic predictors,
and biochemical markers associated with the
development of CHF: relationship to RA
Risk factors for congestive heart failure
The risk factors and biochemical markers associated with the
development of CHF in the general population are listed in
Table 2 Although no systematic investigation has been
performed to dissect the relative contribution of each of these
factors to the development of CHF in RA, several
well-defined contributing factors have been shown to be
over-represented in RA Whether the increased risk of CHF in RA
is primarily due to the effects of known risk factors, or to
unidentified risk factors unique to RA, is currently unknown,
though the predictors analyses by Wolfe et al [27] and
Nicola et al [26] (discussed above) suggest that both
traditional and RA-specific risk factors for CHF are operative
The available evidence on the prevalence of some of these
important risk factors for CHF in RA is reviewed below,
though it is important to recognize that RA is a heterogeneous disorder, and some factors may represent different risks for different subpopulations of RA patients
Hypertension
Systemic hypertension is one of the most potent risk factors for CHF, conferring a two- to three-fold increase in CHF risk for affected individuals [31] Chronic hypertension promotes the development of CHF by a variety of mechanisms, including the induction of maladaptive myocardial remodeling and atherosclerosis Reports of the prevalence of hypertension in RA have yielded varied results, with authors reporting lower [32], equivalent [26,33,34], or elevated [3,24,35] mean systolic and/or diastolic blood pressures in
RA patients compared to matched controls Importantly, although any history of hypertension was strongly associated
with prevalent CHF in the study by Wolfe et al [27] (odds
Table 2 Established risk factors and associative markers for the development of congestive heart failure
Shown to be comparatively
Clinical risk factors
Coronary atherosclerosis/myocardial infarction +++
Intrinsic pulmonary disease +(+) Sleep apnea/sleep-disordered breathing +(?)
Echocardiographic predictors Asymptomatic left ventricular enlargement + Increased left ventricular mass + Asymptomatic left ventricular systolic dysfunction (+)/–
Left ventricular diastolic dysfunction +++
Biochemical risk markers
Medications Non-steroidal anti-inflammatory drugs ++
Rare causes of CHF in the general population
CHF, congestive heart failure + evidence for increased prevalence;
–, no evidence for increased prevalence; +/–, evidence equivocal for increased prevalence; +(?), questionable/insufficient evidence for increased prevalence
Trang 4ratio 2.6 (95% CI 2.1-3.2)), Nicola et al [26] found no
association between hypertension and risk of incident CHF in
RA patients followed for a median of 11.8 years
Additionally, other factors over-represented in RA patients,
such as the chronic use of non-steroidal anti-inflammatory
drugs and corticosteroids, are both known to promote fluid
retention and elevate systemic blood pressure [36] The
independent effect of these agents on the development of
CHF in RA is complex, however, and has yet to be directly
investigated
Coronary atherosclerosis/myocardial infarction
Myocardial infarction (MI) is the most potent risk factor for
CHF, with a population-attributed risk for the development of
CHF in the Framingham cohort of 34% for men and 13% for
women [31] In most cases, other risk factors for CHF (e.g.,
hypertension, diabetes, and smoking) also contribute to the
pathogenesis of coronary atherosclerosis Importantly,
unrecognized and silent MI represents up to 25% of all
myocardial ischemic events [37] and subclinical
athero-sclerosis (with no history of MI) is also associated with an
increased risk for the development of CHF [38]
Several studies have confirmed an approximately two- to
four-fold increase in risk for MI among RA patients compared to
non-RA controls [3,5,34] Wolfe et al [27] showed that
recent MI (within six months) and any history of MI were both
significant univariate correlates of prevalent CHF in RA
patients (odds ratio 16.1 (95% CI 11.0-23.7) and 6.6 (95%
CI 5.4-8.0), respectively) In the study by Nicola et al [26],
ischemic heart disease (including overt MI, silent MI, and
angina) and risk factors for CVD accounted for the risk of
incident CHF in RF negative, but not RF positive, RA patients
Subclinical atherosclerosis, as measured by carotid
ultrasound, is more prevalent in RA patients compared to
matched controls [39] However, the relationship of
subclinical atherosclerosis to the risk of CHF (in the absence
of clinically recognized ischemic heart disease) in RA patients
is currently unknown
Diabetes
Although diabetes is a well-recognized risk factor for the
development of CHF [40,41], the prevalence of diabetes
does not appear to be increased in RA patients compared to
non-RA controls [24,42] Glucose intolerance/peripheral
insulin resistance has, however, been associated with an
increase in CHF risk in both cross-sectional [43] and
prospective, population-based [40] studies, and may be
increased in RA [44,45]
Valvular heart disease
Hemodynamically significant cardiac valvular disease may
lead to overt CHF through maladaptive compensatory
mechanisms resulting in myocardial remodeling (the
molecular basis of which is discussed below) Both necropsy [46] and cross-sectional echocardiographic studies [47] of
RA hearts have identified an increased prevalence of granulomatous and non-granulomatous valvular abnormalities, particularly of the mitral valve, and an increased prevalence of mitral regurgitation in RA patients compared to matched
non-RA controls No longitudinal echocardiographic studies have been performed, however, to determine the impact of this finding on the subsequent risk for developing CHF in affected
RA patients Destructive valvular lesions leading to complete valvular incompetence have been reported [48,49] but are considered rare occurrences
Intrinsic pulmonary disease
A wide spectrum of intrinsic pulmonary disorders, including disorders of the pulmonary air-spaces (chronic obstructive pulmonary disease), parenchyma (interstitial lung disease, pulmonary fibrosis), and vasculature (primary pulmonary hypertension) are associated with increasing pulmonary vascular resistance, progressive hypertrophy of the right ventricle, and eventual right heart failure with clinical CHF [50] In RA, pulmonary disease may be a manifestation of the
RA disease process itself or a result of RA-directed therapies (methotrexate, D-penicillamine, gold and others) [51] While symptomatic chronic pulmonary diseases are more prevalent
in RA patients compared with non-RA controls [24,52], subclinical pulmonary disease, including airways disease [53] (bronchiectasis, bronchiolitis) and parenchymal disease (interstitial pneumonitis), have been noted in nearly 50% of unselected RA patients in one series [54] In addition, several echocardiographic studies have suggested higher right ventricular systolic pressures in RA patients compared to
non-RA controls [55-57] In the study by Dawson et al [56],
pulmonary parenchymal disease could only account for 6% of
RA cases with increased pulmonary arterial pressures, suggesting that asymptomatic primary pulmonary vascular disease may be under-appreciated in RA These findings, and their putative effect on the subsequent development of CHF, warrant further study
Sleep apnea/sleep-disordered breathing
Although sleep apnea has been shown to be highly prevalent
in people with CHF in cross-sectional studies [58], no prospective population-based studies, to date, have investigated the putative effect of sleep apnea on the risk of CHF Sleep apnea is known, however, to increase systemic blood pressure via hypoxia-induced activation of the sympathetic nervous system [59], increase right ventricular pressure via hypoxia-induced pulmonary vasoconstriction [60], potentiate hypoxia-induced coronary ischemia [61], and induce the production of inflammatory cytokines such as IL-6 and tumor necrosis factor (TNF)-α [62], all recognized contributors to CHF risk Few studies of sleep apnea in RA exist, though the disorder has been reported in RA in the context of cervical spine and temporomandibular joint involvement [63] Recent reports of substantial improvements
Trang 5in sleep apnea-associated daytime somnolence in patients
treated with TNF inhibitors [64,65] suggests that the problem
may be under-appreciated in RA At present, however, any
link between sleep apnea and CHF risk in RA is speculative
Other factors
Smoking and obesity are established risk factors for both RA
[66] and CHF [41,67] Both are thought to promote CHF
primarily through exacerbation of atherogenesis, though both
may also potentiate the release of agents with direct toxicity to
the myocardium itself [68,69] Interestingly, although RA
patients may have similar or lower body mass indices than
non-RA counterparts, loss of skeletal muscle mass
accompanied by a compensatory increase in total fat mass in
RA patients may account for the stability of body mass indices
[70] Though no focused investigations have been undertaken
to date, this condition, termed sarcopenic obesity, could
predispose RA patients to higher than expected CHF risk
Rheumatoid arthritis associated factors
In general, myocardial nodules, restrictive pericarditis, and
coronary vasculitis are exceedingly rare causes of CHF [71];
however, older necropsy studies of RA hearts [32,46,72] have
indicated a higher prevalence of each of these complications
compared to the hearts of autopsied non-RA patients More
recent series using transthoracic echocardiography [55,56]
have identified a much lower prevalence of pericarditis than
that reported in the autopsy studies (2% versus 29% to 40%)
In a series using transesophageal echocardiography [47],
however, thirteen percent of RA patients were found to have
clinically silent pericarditis versus zero percent of non-RA
controls Case reports of rheumatoid nodules [73,74],
restrictive pericarditis [75,76], and coronary vasculitis [77] in
RA patients resulting in CHF are not uncommon in the
literature, although it is likely that these entities account for
only a small portion of the excess cases of CHF in RA
Echocardiographic predictors of congestive heart failure
Several large prospective studies have identified
asympto-matic left ventricular (LV) enlargement, hypertrophy and
dysfunction as significant risk factors for the development of
CHF [78-80] The strength of these associations, combined
with the documented efficacy of angiotensin converting
enzyme inhibitor therapy in delaying disease progression,
have prompted consensus recommendation of medical
treatment for these conditions classified as subclinical stages
of CHF [81] Importantly, once global alterations of LV
architecture and function are established, progression to
CHF with functional deterioration and eventually death is
inexorable [82] This unfavorable evolution highlights the
need to define earlier stages of myocardial dysfunction,
particularly in individuals with known risk factors for CHF
CHF with preserved systolic function
Between 30% and 50% of patients with CHF have preserved
systolic function (defined as LV ejection fraction (LVEF)
≥ 45-50%) [83,84] Despite the fact that this condition is associated with lower mortality when compared to heart failure with reduced LVEF, patients with CHF and normal LVEF have a four-fold increase in mortality relative to the normal population [83] In asymptomatic individuals, diastolic dysfunction with preserved systolic function is also predictive
of the subsequent development of overt CHF [85]
To date, a number of Doppler echocardiographic studies have been performed in RA patients without clinical evidence of CHF [55,86-94] (Table 3) Although limited by small numbers of patients and, in some cases, failure to provide a non-RA comparator group, these studies are consistent in demon-strating a high prevalence of asymptomatic diastolic dysfunction
in the setting of generally preserved systolic function A correlation between the degree of diastolic dysfunction and RA disease duration was shown in several investigations [92,94] Without longitudinal assessments, however, few conclusions can be made about the long-term effects of RA disease activity
on cardiac structure and function or, more importantly, factors influencing the transition from asymptomatic myocardial dysfunction to clinical CHF in RA
Impaired diastolic filling is felt to relate physiologically to impair-ment in relaxation or compliance of the left ventricle, resulting in elevated LV filling pressures and resultant elevated back pressures through the pulmonary circulation, right heart, and beyond [95] Histologically, processes that tend to stiffen the myocardium (e.g., hypertrophy, fibrosis, or infiltrative diseases)
or reduce compliance (e.g., restrictive pericarditis) can manifest
as diastolic dysfunction We postulate that chronic low-grade myocardial inflammation resulting in fibrosis may predispose patients with RA to diastolic dysfunction (discussed below)
The limitations of standard echocardiography, which include poor endocardial definition, lack of inter-observer reproducibility
of ejection fraction estimates, and lack of standardization of diagnostic criteria for diastolic dysfunction [96], often make it difficult to be precise about the diagnosis of diastolic dysfunction In practice, however, the diagnosis of diastolic CHF
is generally based on the finding of typical symptoms and signs
of CHF in a patient who is shown to have a normal LVEF and no valvular abnormalities on echocardiography [84] Newer noninvasive imaging methods, including contrast echocardio-graphy and cardiac magnetic resonance imaging, have been developed that permit greater precision and accuracy in the assessment of myocardial function Accordingly, the incorpora-tion of these newer imaging modalities into studies exploring CHF in RA may not only serve to improve diagnostic accuracy, but also provide predictive power and insights into the underlying pathophysiologic mechanisms of disease
Biomarkers associated with congestive heart failure risk
Cardiac natriuretic hormones
Recently, the measurement of circulating levels of brain natriuretic peptide has become available as a means of
Trang 6identifying patients with elevated LV filling pressures who are
likely to exhibit signs and symptoms of CHF Although the
role of cardiac natriuretic hormones in the identification and
management of individuals with asymptomatic ventricular
dysfunction remains to be fully clarified [97], elevated serum
levels of brain natriuretic peptide and amino-terminal pro-atrial
natriuretic peptide have been associated with an increased
risk of subsequent CHF in a community-based epidemiologic
study [98] In one small-scale cross-sectional study, RA
patients were found to have higher serum atrial natriuretic
peptide levels than healthy, non-RA controls [99] Another
cross-sectional study suggested that brain natriuretic peptide
levels may be elevated in RA patients independent of overt or
subclinical myocardial dysfunction [100] To date, no studies
have been performed in RA patients to establish the role of
cardiac natriuretic hormones in either risk stratification or
diagnosis of CHF
Hyperhomocysteinemia
Elevated serum levels of homocysteine have been
independently linked to an increased risk of CHF [101],
particularly in women [102] Hyperhomocysteinemia may
promote the development of CHF through induction of
atherosclerosis [103] and by direct effects on the
myo-cardium leading to myocardial remodeling [102] (discussed
below) In RA patients, homocysteine levels have been shown
to be significantly higher than those of matched non-RA controls [104] and are associated with both markers of inflammation and therapy with methotrexate [105] Though folic acid treatment reduces homocysteine levels in RA patients [105], and combination therapy with methotrexate and folic acid has been recently shown to be associated with
a reduced incidence of CVD in veterans with RA [106], the complex relationship of RA-induced and RA therapy-induced hyperhomocysteinemia to CHF risk in RA has yet to be completely elucidated
Inflammatory cytokines
In patients with overt CHF, levels of inflammatory cytokines (TNF-α, IL-6 and/or TNF-α receptors) are elevated and correlate with the severity of the disease [107-112] regard-less of etiology of CHF In patients with no overt CHF or history of ischemic heart disease, those with the highest serum levels of IL-6, C-reactive protein (CRP), and peripheral-blood mononuclear cell TNF-α were shown to have a two- to four-fold higher risk of developing CHF compared to patients with the lowest baseline levels of these cytokines [113,114]
In patients with overt CHF, both circulating peripheral-blood mononuclear cells and cells localized to the myocardium, including infiltrating inflammatory cells and cardiac myocytes,
Table 3
Doppler echocardiographic studies in patients with RA
Publication No of RA No of control Reference year patients subjects Findings (RA compared to control)
Mustonen et al [86] 1993 12 (males; 14 (males only; LV diastolic functional impairment
age 20-40 years) unmatched) No differences in LV systolic function
Corrao et al [88] 1996 40 40 non-RA Increased interventricular septal thickness
Increased LV mass index
LV diastolic functional impairment
Wislowska et al [89] 1998 100 100 non-RA Increased LV diastolic diameter
Reduced LV ejection fraction
Montecucco et al [90] 1999 54 54 non-RA Impaired diastolic relaxation
No differences in LV systolic function or LV diastolic diameter
Wislowska et al [91] 1999 35 with 35 with Increased valvular disease in nodular RA
nodular RA non-nodular RA Decreased LV ejection fraction in nodular RA
Di Franco et al [92] 2000 32 33 non-RA LV diastolic functional impairment
(unmatched) Positive correlation with RA disease duration (r = 0.40)
Cindas et al [87] 2002 40 48 non-RA LV diastolic functional impairment
Longer disease duration with more abnormal echocardiographic parameters noted
Alpaslan et al [93] 2003 32 with long 32 non-RA LV diastolic functional impairment
standing RA (unmatched) Normal systolic function in all
Levendoglu et al [94] 2003 40 – LV diastolic functional impairment
Positive correlation with RA disease duration Gonzalez-Juanatey 2004 47 treated 47 LV diastolic functional impairment
et al [55] RA patients Positive correlation with extra-articular manifestations of RA
LV, left ventricular; RA, rheumatoid arthritis
Trang 7have been shown to be the source of the elevated cytokine
levels [112,115,116]
In the inflamed synovium of the rheumatoid joint,
macrophage-derived cytokines such as TNF-α, IL-1 and IL-6
are prominently expressed, and inhibitors of these cytokines,
particularly TNF inhibitors, have been proven to be highly
successful therapies for RA [117-120] In RA, the inflamed
synovium as well as peripheral-blood mononuclear cells
contribute to elevated circulating TNF-α (and TNF receptor)
levels To date, however, the potential contribution of the
myocardium in RA as a source of local cytokine production
has not been investigated
Other conditions associated with chronically elevated levels
of inflammatory cytokines (e.g., aging, chronic kidney disease,
obesity) are also associated with an increased prevalence of
CHF [121,70]; however, as in RA, the contributions of
various non-inflammatory confounders in each of these
conditions to the pathogenesis of CHF have not been fully
explored
Clinical studies of TNF inhibitors and
congestive heart failure
The potent association of inflammatory cytokines with both
CHF risk and clinical worsening of existing CHF has
prompted speculation that pharmacologic cytokine inhibition
might prove an effective treatment for established
symptomatic CHF and/or reduce the risk of developing CHF
in patients who are potentially at risk for CHF secondary to
chronic cytokine excess (i.e., patients with RA and other
chronic systemic inflammatory disorders) The unfavorable
and unanticipated results of clinical trials investigating the
use of anti-TNF-α therapy to treat advanced CHF, however,
have raised concerns that TNF inhibitors may actually be
harmful to the myocardium To address this apparent
contradiction we next examine the conflicting human clinical
experience relating TNF inhibitors to CHF in the context of
the available animal data on cytokine-induced CHF
Use of TNF inhibitors as a treatment for advanced
congestive heart failure
Both etanercept, a soluble decoy TNF receptor, and
infliximab, a chimeric anti-TNF-α monoclonal antibody, have
undergone efficacy and safety evaluations in multicenter,
double-blind, placebo-controlled trials for the treatment of
patients with advanced symptomatic CHF [122,123] The
study designs of these trials (‘RENNAISSANCE’
(Randomized Etanercept North American Strategy To Study
Antagonism Of Cytokines) and ‘RECOVER’ (Research Into
Etanercept: Cytokine Antagonism In Ventricular Dysfunction
Trial) [123] for etanercept, and ‘ATTACH’ (Anti-TNF-α
Therapy Against Chronic Heart Failure) [122] for infliximab)
have been recently reviewed in detail [124] The collective
results of the trials were generally unfavorable, with
RENNAISSANCE and RECOVER halted in June 2001 when
an interim analysis revealed that continuation would be highly unlikely to show a statistically significant difference in outcomes between the treatment groups [123] and ATTACH demonstrating no clinical efficacy of infliximab, but higher rates of hospitalizations and all-cause mortality in patients treated with the highest dose (10 mg/kg) of infliximab compared to placebo [122]
The high-profile and well-publicized nature of these trials, coupled with a 2002 report, using the US Food and Drug Administration’s MedWatch post-licensure database for voluntary reporting of adverse events, of new or worsening CHF in 47 of approximately 300,000 patients worldwide treated with infliximab or etanercept (of whom 38 (81%) had
no prior history of CHF, and 10 of whom were less than
50 years of age) have led some to conclude that TNF inhibition may exert a detrimental, rather than protective, effect on the myocardium of RA patients To date, the only available evidence to refute this supposition comes from
Wolfe et al [27], in which a statistically significant lower rate
of self-reported, physician-diagnosed CHF was determined in
RA patients receiving treatment with a TNF inhibitor compared to those not treated with TNF inhibitors, even after adjustment for unbalanced clinical characteristics and previous history of CVD (2.8% versus 3.9%, respectively,
P = 0.03) A lower rate of incident CHF in TNF inhibitor
treated versus untreated patients was also demonstrated (3.5% versus 4.3%, respectively) when the analysis was limited only to data collected after the Food and Drug Administration warning following the RENNAISANCE, RECOVER, and ATTACH trials, although this difference was not statistically significant No cases of incident CHF in TNF inhibitor treated RA patients who were less than 50 years of age were found, although three cases of incident CHF were reported in RA patients under 50 years of age who were not treated with TNF inhibitors As noted above, the diagnosis of CHF in this study was not based on predefined clinical and/or imaging criteria nor was the etiology of CHF (ischemic versus non-ischemic versus other) determined; nonetheless, this study provides tantalizing circumstantial support for the notion that TNF-α contributes to the etiology of CHF in RA Additional indirect support derives from a recent report [125]
in which the prescription of disease modifying antirheumatic drugs (DMARDs; including TNF inhibitors) was associated with a 30% reduction in hospitalizations for new-onset CHF from a large administrative claims database of RA patients Considering only TNF inhibitor treated patients, a 50% reduction in CHF hospitalizations was observed
To date, few human investigations into the direct effects of TNF-α or TNF inhibitors on the myocardium have been under-taken Imaging substudies of non-RA patients with advanced CHF showed no effect of etanercept on LVEF (assessed in
215 subjects who underwent radionuclide ventriculography
at baseline and at 24 weeks) in RENNAISANCE [126] and a modest increase in LVEF (measured by radionuclide
Trang 8ventriculography) despite clinical worsening in infliximab
treated patients in ATTACH [122] Although studies
incorporating direct visualization of myocardial function have
yet to be performed in RA patients, clues from animal models
of CHF induced by chronic cytokine excess (a setting that
may mimic the RA disease state) may serve to explain the
apparent contradictions in treatment effects of cytokine
inhibition on the myocardium
Animal models of cytokine induced
congestive heart failure
In vitro and animal studies strongly support a mechanistic
role for macrophage-derived cytokines, especially TNF-α, in
the pathogenesis of CHF, rather than a mere
epipheno-menon Key features of the CHF phenotype, including
pulmonary edema, negative inotropy, ventricular dilatation and
hypertrophy, endothelial dysfunction, reduced myocardial
β-adrenergic responsiveness, and myocyte apoptosis are
recapitulated by experimental augmentation of TNF-α
[127-129] In a rat model, continuous infusion of TNF-α via an
implanted osmotic infusion pump to levels congruent with
those found in human CHF, led to a time-dependent
reduction in LVEF and development of left ventricular
dilatation [130] These effects were reversed, at least in part,
by removal of the infusion pump or administration of a dimeric
TNF receptor antagonist [130]
Transgenic murine models of cardiac-restricted
over-expression of TNF-α have been generated by coupling the
murine TNF-α gene to the murine α-myosin heavy chain
promoter [131-133] When expression is extremely robust,
the animals die quickly (mean 11 days) of a dilated
cardio-myopathy that, on histologic examination, is due to a diffuse
inflammatory myocarditis [131] With less robust expression
of TNF-α, survival is longer (mean time to death approximately
10 months) and the CHF phenotype evolves more gradually,
characterized by ventricular hypertrophy and dilatation,
interstitial infiltrates and fibrosis, and depressed adrenergic
response These effects were attenuated or blocked by
antagonism of TNF-α [134-136]
These studies strongly support a central role for TNF-α in
mediating the processes leading to myocardial dysfunction
An inflammatory myocarditis has also been described in
autopsy studies of RA patients (discussed above) It is
tempting to speculate that chronic production of cytokines,
including TNF-α, may affect the myocardium in RA in either an
endocrine (originating in the synovium) or paracrine (produced
in the local environment of the progressively failing
myocardium) fashion, contributing to subclinical and eventually
clinically recognizable ventricular dysfunction (Fig 1)
Inflammatory pathways and myocardial remodeling
The process by which cardiac structure and function adapts
to physiologic changes is termed ‘myocardial remodeling’ and
involves the cellular and interstitial changes leading to
myocyte hypertrophy, ventricular dilatation, alterations in interstitial collagen superstructure, and interstitial myocardial fibrosis [137] This process is mediated primarily through local expression of matrix metalloproteinases (MMPs), particularly MMP-1, MMP-2, MMP-3, and MMP-9, and modulated by expression of tissue inhibitors of matrix metalloproteinases (TIMPs) [138] Circulating levels of MMPs are elevated in patients with overt CHF, regardless of etiology [139-141], suggesting a common unifying mechanism Overexpression of MMPs and/or reduced expression of TIMPs are associated with proteolysis of the myocardial extracellular fibrillar collagen matrix and progressive ventricular dilatation [142,143] Selective and non-selective MMP inhibition reverses or blocks the development of the phenotype [144,145]
TNF-α has been shown to be a key regulator of MMP expression in myocardial remodeling [135,146] In transgenic mice with cardiac restricted overexpression of TNF-α [146], early exposure to elevated TNF-α was associated with an increase in the myocardial zymographic MMP activity/ myocardial TIMP (MMP/TIMP) ratio favoring degradation of interstitial fibrillar collagen and development of ventricular dilation and CHF With aging, however, a shift to increased myocardial TIMP levels and an overall reduction in the MMP/
Figure 1
Proposed pathogenesis of myocardial dysfunction in rheumatoid arthritis CRP, C reactive protein; DMARD, disease modifying anti-rheumatic drug; IL, interleukin; MMP, matrix metalloproteinase; NSAID, non-steroidal anti-inflammatory drugs; TNF, tumor necrosis factor
Trang 9TIMP ratio, an increase in collagen production, and
subsequent fibrosis of the dilated ventricle was observed
This later phase was associated with an increase in
transforming growth factor-β expression [146] This
time-dependent effect of TNF-α induced myocardial remodeling
suggests that there may be a window of opportunity early in
disease during which events leading to myocardial interstitial
fibrosis may be prevented [147] Importantly, it is this shift
from myocardial interstitial degradation to fibrosis that
appears to play a key role in the transition from compensated
to decompensated CHF [148] Moreover, this is supported
by the finding that delayed anti-TNF-α therapy, administered
at six weeks of age, was able to reverse ventricular dilatation,
but not established fibrosis, in a transgenic mouse model of
cardiac TNF-α overexpression [149] The possibility that
enhancing TNF-α expression in late CHF might even be
desirable in order to reestablish a favorable MMP/TIMP
balance has not been explored
Recent work suggests that cardiac structural homeostasis is
regulated in part through a balance between
membrane-bound and cleaved TNF-α Normally, membrane membrane-bound
TNF-α is converted to its soluble form by cleavage with
TNF-α converting enzyme (TACE) [150] In a line of
transgenic mice with cardiac-restricted overexpression of
TNF-α that is resistant to cleavage by TACE, concentric
hypertrophy without chamber dilatation was observed
[151,152], whereas mice with overexpression of TNF-α and
an intact TACE cleavage site exhibited extracellular matrix
degradation and ventricular dilatation [151,152] In humans,
increased TACE expression parallels the increase in TNF-α
expression associated with dilated cardiomyopathy [153] and
myocarditis [154] Little is currently known, however, about
the relative amounts or contribution of membrane bound
TNF-α to myocardial homeostasis in humans
In summary, animal studies have shown that the processes
leading to cardiac myocyte hypertrophy, interstitial fibrillar
collagen degradation, mural realignment, and ultimately to
dilated cardiomyopathy are induced and/or regulated, at least
in part, by TNF-α The effects of TNF-α on the myocardium
are complex, however, with a pathogenic effect early on and a
putative protective effect later in disease This dichotomy has
important potential implications for human disease and has
preliminary support from available clinical studies of TNF
inhibitors in humans, in which patients with advanced CHF
have shown no benefit or worsened when treated with
anti-TNF-α therapy In contrast, in patients with RA and no overt
CHF, treatment of RA with TNF inhibitors might offer some
protection against cytokine induced CHF
Conclusions
The evolution of subclinical myocardial dysfunction to overt
CHF is associated with significant morbidity and alarming
mortality Population- and clinic-based epidemiologic studies
have suggested that RA patients may be more prone to the
development of CHF and more susceptible to CHF-related mortality While some traditional risk factors for CHF are over-represented in RA patients, they do not appear to account for all of the increased CHF risk observed Other RA associated factors, particularly the chronic elaboration of inflammatory cytokines, are likely substantial contributors to myocardial dysfunction in RA patients Additional investigation is needed
to clarify both the direct effects of the RA disease process and the effects of RA-directed therapeutics on the myocardium at all stages of disease in order to define appropriate strategies to prevent or attenuate the development of CHF in RA patients
Competing interests
Dr Giles receives grant support from the American College of Rheumatology and the Arthritis National Research Foundation
Dr Bathon receives grant support from the National Institutes
of Health, Bristol Myers Squibb, Centocor, Amgen, IDEC/Genentech Dr Bathon is a consultant to Abbott
Acknowledgments
This work was supported in part by an American College of Rheumatol-ogy Clinical Investigator Fellowship Award (JTG), an Arthritis National Research Foundation Award (JTG), and by Grant AR050026-01 from the National Institute of Arthritis and Musculoskeletal and Skin Dis-eases (JMB)
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